Amphetamine and numerous derivatives, including methamphetamine, have been used therapeutically for many years. These agents are known to have abuse potential which was clearly evidenced in the United states (in the 1950s and 1960s) and in several countries in Asia. A far more frightening specter has no appeared on the horizon, "ice", which is a smokeable form of methamphetamine. Currently, the use of "ice" in Hawaii is as wide-spread as that of crack cocaine. Recent literature has referred to this new threat as, "the drug plague of the 1990s"0. The incidence of its use and reports of toxicity and death have increased dramatically in recent years. The overall aim and long-term objective of this proposal is to obtain information necessary to develop and test rational modes of therapy to treat toxicity due to methamphetamine and its congeners. In order to do disposition kinetics of the drug need to be examined. The rat will serve as the animal model. The acute disposition kinetics will be determined as a function of dose and route (intravenous, oral and smoking). Disposition following chronic dosing will also be determined by selected routes. The pharmacokinetic interaction of methamphetamine with other selected drugs of abuse (known to be coingested by abusers) will be examined: ethanol, cocaine, marijuana. The potential interaction with other compounds will also be examined (e.g., PCP, nicotine, caffeine). From the above information strategies for the treatment of toxicity will emerge and will be tested. A physiological pharmacokinetic model will be developed in order to attempt to relate temporal patterns of disposition to other species including humans. Finally, fetal exposure to methamphetamine will be determined. Future work will examine the disposition of selected congeners of methamphetamine for which there is little or no information; extend the work here to other species including humans and pursue development of a pharmacodynamic-pharmacokinetic model.